Enalapril is a well-known ACE inhibitor. Its chemistry (Medicinal Chem. Rev., 1985, 5, 483), preparation (U.S. Pat. No. 4,374,829), biological transport (Advanced Drug Delivery Rev., 1992, 8, 253), active metabolites (Drug Met. Dispos., 1982, 10, 15). Pharmacology (J. Pharmacol. Exp. Ther,. 1981, 216, 552), Bioavailability (J. Pharmacol. Exp. Ther., 1983, 226, 192), and clinical use in the treatment of hypertension have been reviewed.
Enalapril is typically isolated and purified as the maleate addition salt. Another salt of enalapril which could have pharmaceutically acceptable characteristics is the sodium salt. The sodium salt of enalapril is not easily purified since it is soluble in most organic solvents and in water. In pure form, it is a hydroscopic oil or glass. Sodium enalapril can be prepared by treating the maleate with a sodium alkoxide or sodium hydroxide and selectively crystallizing the disodium salt of maleic acid. The solutions containing pure sodium enalapril thus obtained often contain trace amount of the base used to form the salt. Sodium enalapril undergoes a very facile ester hydrolysis in aqueous media in the presence of base to generate sodium enalaprilat, which is not orally active. Commercial production of pure sodium enalapril is thus very difficult.
It is therefore an object of this invention to provide improved processes for the manufacture of sodium enalapril and intermediates thereof.
It is a further object to provide intermediates suitable for use to manufacture sodium enalapril.
Further and other objects of the invention will be realized by those skilled in the art from the following summary of the invention and detailed description of embodiment.